Do we know about the 48wk data from the PRO051 extension study?

 

Ofelia,

 I noticed your comments on FB about some boys not responding. Do you have any further details?

 

 

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This is the abstract of their presentation at AAN 2011 last week. Good news, the improvement in 6MWT was maintained after 48 weeks, bad news the side effects (protein in urine in ALL boys). Also to note the huge standard deviation which tells that there is a big variation in the 6MWT times in the boys with some improving and some not. I am concerned that FDA will not approve such a drug if they cannot explain the side effects...

 

[S34.004] Forty-Eight Week Follow-Up Data from a Phase I/IIa Extension Study of PRO051/GSK2402968 in Subjects with Duchenne Muscular Dystrophy

Nathalie Goemans, Leuven, Belgium, Mar Tulinius, Gothenburg, Sweden, Rosamund Wilson, Marlborough, Wiltshire, United Kingdom, Judith van Deutekom, Sjef de Kimpe, Giles Campion, Leiden, The Netherlands 

OBJECTIVE: To evaluate the efficacy and safety of 48 weeks of treatment with PRO051/GSK2402968 in boys with Duchenne muscular dystrophy (DMD).BACKGROUND: DMD patients suffer from progressive muscle degeneration due to mutations in the DMD gene and resulting absence of functional dystrophin in the muscle cell wall. PRO051/GSK2402968 is an antisense oligonucleotide compound which induces exon 51 skipping during pre-mRNA splicing and produces novel dystrophin expression in a subpopulation of DMD patients. DESIGN/METHODS: Twelve DMD patients with mutations correctable by skipping exon 51, (11 ambulatory, 1 non-ambulatory at study entry) completed a dose-escalation Phase I/IIa study (Netherlands Trial Register #NTR124) and entered the open-label extension study. Subjects were to receive weekly subcutaneous injections of 6mg/kg of PRO051/GSK2402968 in the extension study, regardless of earlier dose. All subjects were at stable steroid doses during the study. Assessments were performed at baseline and 4-week intervals thereafter. RESULTS:All boys reported treatment-emergent AEs. The most common AEs were increased urinary 1-microglobulin (100%), proteinuria (92%) and injection site reactions (100%). However, the majority of AEs were considered to be mild; there were no severe treatment-related AEs. There was some evidence of mild proteinuria, confirmed as greater than the upper limit of normal range (>0.15g<0.3g/24hrs), in four boys at subsequent 24-hr collection. Increases in some renal and hepatic parameters were observed but none were considered progressive. Four serious AEs (not related to treatment) were reported. There was an improvement in 6-minute walking distance test (6MWD) from 12 weeks; this was maintained until week 48, when the mean (SD) improvement in 6MWD was +29 (80)m. CONCLUSIONS: PRO051/GSK2402968 6mg/kg administered weekly by subcutaneous injection was generally well tolerated across 48 weeks of treatment. Renal and hepatic function warrant further monitoring. As 6MWD is expected to deteriorate over 48 weeks, the improvements observed in this functional measurement are encouraging.

I'm waiting for more details from people attending the meeting.

Thanks Ofelia.

 

In the PTC trials spread over the 48 week period they talked about a 42% decline in 6MWT and achieved 12% decline. Assuming a 360m baseline 6MWT Prosensa's effect would be a range of -15% to +30% . Just by these numbers looks like atleast the progression is getting delayed.

 

Lets wait for more details on the proteinuria which is in the lower side of the limits.

Yes, it looks to me that the progression is delayed...I wish we had more info than this abstract...
I'm with you that extra protein in the urine is troubling, but from my uninformed perspective it does not seem that surprising.  The intended effect of the drug is to stimulate production of a new protein in the boys bodies.  It stands to reason that not all of that protein is going to stick between muscle cells and connective tissue and that some of it is going to float away and get cleared by the kidneys.  I had heard some rumor somewhere that the expectation was that a long term maintenance regimen of these drugs would involve less frequent administration.  Hopefully that will satisfy our fearless "protectors" at the FDA.
This would need to be validated in the AVI trials. If I remember correctly they did not see this side effect? I think the hope is to have weekly injections int he first moths then every 2-3 weeks. I'm assuming that would help...GSK is testing something like this in Phase II in UK now.

Paul Cliff said:
I'm with you that extra protein in the urine is troubling, but from my uninformed perspective it does not seem that surprising.  The intended effect of the drug is to stimulate production of a new protein in the boys bodies.  It stands to reason that not all of that protein is going to stick between muscle cells and connective tissue and that some of it is going to float away and get cleared by the kidneys.  I had heard some rumor somewhere that the expectation was that a long term maintenance regimen of these drugs would involve less frequent administration.  Hopefully that will satisfy our fearless "protectors" at the FDA.

This was posted on another forum:

 

Dr. Wade from WedBush reports..."We view the proteinuria side effect associated with PRO051/GSK2402968 a potential limitation to the treatment, and a barrier to
eventual approval, particularly if the origin and consequences of elevated protein levels are not well understood. We note that
proteinuria is a known side-effect associated with oligonucleotide technologies in general and was not seen in the eteplirsen (AVI-4658)
study, potentially due to the different backbone chemistry of AVII’s PMO technology. Additionally, at this time it is unknown if the
primary outcome is achievable, given the challenges inherent to controlling for the many factors that contribute to the 6-minute walk
distance test results.

I have been trying to read more about this Proteinuria business. Turns out that Prednisone itself has a influence on the proteinurea...at least that what some of the papers say...like the one given below.

 

At this stage it looks like Phase 2 and Phase 3 of Prosensa drug have at least one more data to monitor before we can draw any conclusions on Proteinuria impact of PRO051.

 

 

 

 

Prednisone-induced fluctuations of proteinuria in patients with a nephrotic syndrome.

Abstract

We studied the effect of prednisone on urinary protein excretion in 19 patients with a nephrotic syndrome, who were treated with prednisone (125-150 mg) on alternate days. We found a typical, fluctuating pattern of proteinuria resulting from an increased protein excretion rate on prednisone days and a decreased protein excretion rate on nonprednisone days. The urinary protein excretion on prednisone days was 9.9 +/- 3.3 g/24 h, as compared to 5.7 +/- 3.8 g/24 h on nonprednisone days (mean +/- SD). In the whole group of patients the percentual change in proteinuria was significantly correlated with the endogenous creatinine clearance. However, systematic differences between creatinine excretion rates on prednisone and nonprednisone days were not found in individual patients. In 6 patients, renal hemodynamics were studied more precisely, using a single injection technique. Only a slight and nonsignificant decrease in glomerular filtration rate was found on nonprednisone days (delta = -9.6 +/- 16.3%; mean +/- SD). Filtration fraction remained unchanged. It is therefore suggested that the effects of prednisone on proteinuria are not simply mediated by overall changes in renal hemodynamics.

I also think that the jury is still out on this one. If they are able to create a less often dosing regimen it might help. Good news is that trials continue in Europe, Australia, Japan and Phase III already started.

Tulika said:

I have been trying to read more about this Proteinuria business. Turns out that Prednisone itself has a influence on the proteinurea...at least that what some of the papers say...like the one given below.

 

At this stage it looks like Phase 2 and Phase 3 of Prosensa drug have at least one more data to monitor before we can draw any conclusions on Proteinuria impact of PRO051.

 

 

 

 

Prednisone-induced fluctuations of proteinuria in patients with a nephrotic syndrome.

Abstract

We studied the effect of prednisone on urinary protein excretion in 19 patients with a nephrotic syndrome, who were treated with prednisone (125-150 mg) on alternate days. We found a typical, fluctuating pattern of proteinuria resulting from an increased protein excretion rate on prednisone days and a decreased protein excretion rate on nonprednisone days. The urinary protein excretion on prednisone days was 9.9 +/- 3.3 g/24 h, as compared to 5.7 +/- 3.8 g/24 h on nonprednisone days (mean +/- SD). In the whole group of patients the percentual change in proteinuria was significantly correlated with the endogenous creatinine clearance. However, systematic differences between creatinine excretion rates on prednisone and nonprednisone days were not found in individual patients. In 6 patients, renal hemodynamics were studied more precisely, using a single injection technique. Only a slight and nonsignificant decrease in glomerular filtration rate was found on nonprednisone days (delta = -9.6 +/- 16.3%; mean +/- SD). Filtration fraction remained unchanged. It is therefore suggested that the effects of prednisone on proteinuria are not simply mediated by overall changes in renal hemodynamics.

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